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J I DeGraw

Publications and source records attributed to J I DeGraw.

At least 37 records · Page 2Linked to original sources
PubMed1986

Synthesis and antifolate properties of 5,10-methylenetetrahydro-8,10-dideazaminopterin.

The synthesis of the 5,10-methylene analogue of 5,6,7,8-tetrahydro-8,10-dideazaminopterin, a potential dual inhibitor of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzymes, is described. The dimethyl ester of 10-carboxy-4-amino-4-deoxy-8,10-dideazapteroic acid was converted to the tetrahydro derivative by hydrogenation. Thermally induced cyclization of the 10-carbomethoxy and the 5-NH groups afforded the 5,10-carbonyl analogue. Reduction of the lactam with borane readily yielded the key 5,10-methylene-4-amino-4-deoxy-8,10-dideazatetrahydropteroic acid methyl ester. Saponification of the benzoate ester and coupling with L-glutamate concluded the synthesis. The title compound was a modest inhibitor of growth in folate-dependent bacteria. Streptococcus faecium and Lactobacillus casei, but inhibition of DHFR or TS derived from L. casei was poor. The compound was also a weak inhibitor of DHFR derived from L1210 murine leukemia and was a weak inhibitor of L1210 growth in culture.

Aminopterin↗
PubMed1985

Metabolic and toxicologic study of an artificial sweetener, oxime V.

Metabolic disposition and subchronic oral toxicologic studies were conducted on a new synthetic sweetener, Oxime V. Based on radioactivity assay, the compound was readily absorbed and metabolized. Excretion was nearly quantitative 48 hours after dosing the rat, dog, and rhesus monkey. The major metabolites were formed by oxidation and reduction of the cyclohexadiene ring, oxidation of the aldoxime and dimethyl ether moieties followed by conjugation with glycine, thiomethylation of the ring, and O-glucuronidation of the aldoxime. A two-month feeding study was conducted with male adult rats. The average consumption of Oxime V was 396.5 mg/kg per day by rats fed a diet containing 0.6% of the test compound. No treatment related histopathologic lesion was observed in the liver, kidney, spleen, and testes. The liver weight relative to the body weight and serum bilirubin level were increased.

Animals↗
PubMed1985

New folate analogs of the 10-deaza-aminopterin series: markedly increased antitumor activity of the 10-ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice.

In an extension of our prior studies in murine tumor models, we examined two new folate analogs in the 10-deaza-aminopterin series for antitumor activity against a group of human tumor xenografts in nude mice. In all three xenograft models studied, MX-1 mammary carcinoma, LX-1 lung carcinoma, and CX-1 colon carcinoma, 10-deaza-aminopterin was minimally active, while methotrexate was inactive. In contrast, against the MX-1 and LX-1 tumors, 10-ethyl, 10-deaza-aminopterin at or near the LD10 dose (2-4.5 mg/kg) given once per day X 5 produced frank regressions. Activity of this analog against the CX-1 tumor was less, but retardation of tumor growth was observed with some minor regressions.

Aminopterin↗
PubMed1984

New folate analogs of the 10-deaza-aminopterin series. Basis for structural design and biochemical and pharmacologic properties.

Structural modification of the N10 position of 4-amino folates affects mediated membrane transport in mammalian cells but has little or no effect on target enzyme (dihydrofolate reductase) inhibition. Some of these modifications have been associated with differential effects on transport in various cell types in a manner which favored greater accumulation and persistence of drug in responsive tumor cells than in normal proliferative tissue. With the aid of identifying new structures with greater potential for differential mediated accumulation, we have studied three new 10-alkyl analogs of 10-deaza-aminopterin. Two of these analogs showed therapeutic efficacy substantially greater than 10-deaza-aminopterin, an analog with antitumor properties superior to methotrexate. These analogs, the 10-methyl, 10-ethyl, and 10,10-dimethyl derivatives, were equivalent to the parent compound, 10-deaza-aminopterin, and aminopterin, and slightly more potent than methotrexate, as inhibitors of L1210 cell dihydrofolate reductase. The three new analogs, 10-deaza-aminopterin, and aminopterin exhibited similar transport properties in L1210, Ehrlich, and S180 cells. Efflux and influx Vmax were similar to those of methotrexate, but influx Km was 4- to 14-fold lower than for methotrexate. That is, substitution at N10, but not at C10, reduced influx potential in these tumor cells. These differences in transport properties among this group of analogs which determine net accumulation were reflected in the individual values for growth-inhibitory potency. In contrast to that seen in tumor cells, alkylation at both N10 and C10 reduced influx potential (increased Km) in isolated intestinal epithelial cells from mouse small intestine. Influx was in the order aminopterin greater than 10-deaza-aminopterin with further reduction in each series showing a magnitude in proportion to the size of the 10 substituent. Otherwise, influx Vmax and efflux were similar for the group. Accumulation of polyglutamates in small intestine was greater following aminopterin administration than following administration of other analogs (10-ethyl, 10-deaza-aminopterin less than methotrexate less than 10-deaza-aminopterin). Polyglutamate accumulation for all the analogs was greater in tumor cells, but accumulation of each varied between the two tumors (L1210 and S180) examined. Differences among the analogs were not as great in L1210 as in S180 cells, and their metabolism was not in the same relative order.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminopterin↗
PubMed1984

Synthesis and antifolate properties of 10-alkyl-8,10-dideazaminopterins.

The synthesis of 10-alkyl analogues of the potent antitumor agent 8,10-dideazaminopterin is described. Alkylation of appropriate alpha-alkyl homoterephthalate esters with 2,4-diamino-6-(bromomethyl)-8-deazapteridine afforded 10-alkyl-10-carboxy-4-amino-4-deoxy-8,10-dideazapteroic acid diesters. Ester cleavage and decarboxylation at C-10 were accomplished by heating with sodium cyanide in Me2SO at 170-180 degrees C to afford the 2,4-diamino-10-alkyl-8,10-dideazapteroic acids. The acids were coupled with diethyl glutamate, followed by saponification, to give the 10-alkyl-8,10-dideazaminopterins. The compounds were potent inhibitors of growth in folate-dependent bacteria, Streptococcus faecium and Lactobacillus casei. The 10-methyl and 10-ethyl analogues gave the highest percent increases in life span for mice infected with L1210 leukemia with ILS values of +203 and +235%, respectively.

Aminopterin↗
PubMed1984

Similar specificity of membrane transport for folate analogues and their metabolites by murine and human tumor cells: a clinically directed laboratory study.

Mediated transport of folate compounds exhibited similar kinetic characteristics and structural specificity in a series of cultured murine and human tumor cells examined in a parallel fashion. In each case, influx was characterized by a single saturable component with an approach to steady-state conforming to a single exponential, while efflux was first order (poorly saturable). Both mediated fluxes exhibited high temperature dependence (Q10 27-37 degrees = 6 to 8). During competition studies with various analogues, it was found that positions 4, 5, 7, and 10 and the gamma-carboxyl position of the folate molecule were specified for influx in tumor cells from each species. Also, short-chain alkyl substitution at position 10 was specified in the case of N10, but not in the case of C10. None of the modifications at position 10 affected mediated efflux in either cell type. The linkage of additional glutamyl residues at the gamma-carboxyl-position resulted in reduced saturability (increased value for Ki) of influx in both murine and human tumor cells in a manner proportional to the number of glutamyl residues. Mediated influx in human ovarian carcinoma cells obtained from malignant effusions in several patients and in an established cell line derived from one of these patients showed similar kinetics for folate analogue transport and specificity for modification at position 10 of the 4-amino-folate molecule. Mediated entry of 10-deazaaminopterin and its 10-ethyl derivative compared to entry of methotrexate was 4- to 11-fold greater in murine tumor cells and 4- to 9-fold greater in human tumor cells in culture or when clinically derived. Mediated efflux was not specified for position 10 on the 4-amino folate structure in any tumor cell type. These findings appear to provide some basis for concluding that the results of studies of this type in model murine systems or with tumor cell lines established in culture have relevance to clinical cancer.

Animals↗
PubMed1984

New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid murine tumor models.

A group of folate analogs of the 10-deaza-aminopterin series, which were designed on the basis of the results of an intensive biochemical and pharmacokinetic program, have been examined in therapy experiments utilizing a group of murine tumor models. These new analogs were found to be markedly superior to methotrexate against four of five ascites tumors (L1210 leukemia, Sarcoma 180, Ehrlich carcinoma and Tapper carcinosarcoma) and against four of five solid tumors (S180, Tapper carcinosarcoma, E0771 mammary adenocarcinoma, Lewis lung carcinoma, and T241 sarcoma). Analogs alkylated (methyl or ethyl) at the 10 position of 10-deaza-aminopterin were found to be the most effective of the group. These analogs achieved log10 reduction in tumor burden several-fold greater in magnitude than methotrexate against L1210 and S180 ascites tumors and there were also long-term survivors. 10-Deaza-aminopterin itself gave a result intermediate between those obtained with the 10-alkyl derivatives and methotrexate. Against the solid forms of the Tapper tumor some partial regressions were obtained with methotrexate and 10-deaza-aminopterin, but a far greater number, extending over a longer period were obtained with the 10-ethyl derivative of 10-deaza-aminopterin. Against the E0771 tumor, 10-deaza-aminopterin was 2-fold and the ethyl derivative of 10-deaza-aminopterin was greater than 5-fold more effective than methotrexate in retarding tumor growth. Evidence for partial regressions and marked effects against metastatic disease were also obtained in the case of the 10-alkyl derivative. Similar results were also obtained with the T241 sarcoma. For Lewis lung carcinoma the relative potency was about the same but overall antitumor effects were more modest.

Aminopterin↗
PubMed1982

Synthesis and antitumor activity of 10-alkyl-10-deazaminopterins. A convenient synthesis of 10-deazaminopterin.

Requirements for large-scale synthesis of the potent antitumor drug 10-deazaminopterin have led to development of a facile synthesis of this compound and its 10-alkyl analogues. The lithium diisopropyl amide generated dianions of appropriate p-alkylbenzoic acids were alkylated with 3-methoxyallyl chloride. The resulting 4-(p-carboxyphenyl)-1-methoxy-1-butenes were brominated at pH 7-8 to afford the 2-bromo-4-(p-carboxyphenyl)butyraldehydes. Condensation with 2,4,5,6-tetraminopyrimidine and subsequent in situ oxidation of the resulting dihydropteridines yielded crystalline 10-alkyl-10-deaza-4-amino-4-deoxypteroic acids. The pteroic acids were coupled with diethyl glutamate via the mixed anhydride method, followed by saponification at room temperature, to give the target 10-deazaminopterins. The 10-alkyl compounds were approximately equipotent to 10-deazaminopterin as growth inhibitors of folate-dependent bacteria. Their abilities to inhibit Lactobacillus casei and L1210 derived dihydrofolate reductases were also similar. Transport properties in vitro were suggestive of an improved therapeutic index for the 10-alkyl analogues. Against L1210 in mice, the percent increase in life span at the LD10 dosage was +151% (methotrexate), +178% (10-deazaminopterin), +235% (10-methyl analogue), and +211% (10-ethyl analogue). 10,10-Dimethyl-10-deazaminopterin was less effective at an equimolar dosage, but the ILS at the maximum dose tested (72 mg/kg) was +135%. It was far less toxic than the other analogues possibly because of enhanced clearance.

Aminopterin↗
PubMed1978

Analgesics. 1. Synthesis and analgesic properties of N-sec-alkyl- and N-tert-alkylnormorphines.

A series of N-sec- and N-tert-alkylnormorphines was synthesized and evaluated for analgesic potency, antagonist activity, and opiate receptor binding. Computer-assisted conformational analysis profiles were utilized to assist in the selection of compounds for synthesis and correlation of receptor events with in vivo observations. N-tert-Alkylnormorphines 5a-c were devoid of agonist activity; however, some sec-alkyl analogues showed interesting mixed agonist-antagnoist actions. N-sec-Butyl- and N-(alpha-methylally)normorphine were separated into R and S isomers, which exhibited quantitative pharmacological differences. The N-sec-butyl S isomer 10a showed analgesia approximating morphine with nalorphine-like antagonist activity. Preliminary testing indicates only slight evidence for physical dependence with this compound.

Analgesics↗
PubMed1978

Antitumor properties of a new folate analog, 10-deaza-aminopterin, in mice.

A new folate analog, 10-deaza-aminopterin, was substantially more active than methotrexate, following sc administration in mice, against three of five ascites tumors and two of three solid tumors. For ascites tumors, maximum increases in lifespan (using 6--12 mg/kg q2d X 5) with 10-deaza-aminopterin versus methotrexate were + 171.2%/+ 149.8% against L1210 leukemia, +118.4%/+109.1% against P815 plasmacytoma, +64%/+20.9% against Ehrlich ascites carcinoma, +84.2%/+44.8% against Taper liver tumor, and greater than +159.6%/+64.0% against Sarcoma 180 with longterm survivors after 10-deaza-aminopterin. In a smaller number of experiments comparing LD10 dosages (given q2d X 5) of aminopterin, methotrexate, and 10-deaza-aminopterin, aminopterin was the least effective and 10-deaza-aminopterin was the most effective against the L1210 leukemia, Sarcoma 180, and Ehrlich ascites tumors. Following oral administration (3--6 mg/kg q2d X 5), a twofold greater increase in survival time was obtained against the L1210 leukemia with 10-deazaaminopterin (+122.8%) versus methotrexate (+57%). At a dosage of 6 mg/kg q1d X 5 against solid tumors, the relative tumor volumes (treated/control X 100%) were 12%/41% for Sarcoma 180, 16%/31% for Taper liver tumor, and 20%/30% for Ehrlich ascites carcinoma. Overall, the data suggest a broader spectrum of effective antitumor action in mice and a potential for the expanded clinical utility of this category of agent.

Aminopterin↗
PubMed1977

Application of 13C-NMR spectroscopy to in vitro analysis of enzyme kinetics.

The conversion of D,L-alpha-13C-histidine to similarly labeled alpha-13C histamine by bacterial and mammalian histidine decarboxylase was studied by 13C-NMR spectroscopy and GLC-mass spectrometry. The results obtained with the partially purified bacterial enzyme were in essentially perfect agreement with results obtained simultaneously with a standard radioisotopic method using carboxyl-labeled-14C-L-histidine. For a crude tissue preparation of the mammalian enzyme, the radioisotopic method indicated an activity three times that based on 13C-NMR measurement of alpha-13C-histamine. The difference in results was accountable in terms of additional 13C-NMR signals attributable to products other than histamine due in part to enzymatic degradation of the latter.

Animals↗
PubMed1977

Potential histidine decarboxylase inhibitors. 1. alpha- and beta-substituted histidine analogues.

Histidine analogues with alkyl substitution at Calpha and Cbeta were prepared as potential inhibitors of specific histidine decarboxylase. Activity was assessed in vitro using extracts of rat pyloric stomach and a radioisotopic assay of 14CO2 evolved from carboxyl-14C-labeled histidine. alpha-Substituted analogues (C2-C4) including 2-hydroxyethyl were less potent than alpha-methylhistidine; the alpha-n-butyl analogue was completely inactive at 10(-3) M. Similarly, beta,beta-dimethylhistidine and homohistidine failed to exhibit activity at 10(-3) M.

Animals↗
PubMed1975

Synthesis of d-pilocarpine-N-14CH3.

The total synthesis of d-pilocarpine specifically labeled as N-14CH3 is reported. dl-Homopilopic acid was prepared as a key intermediate and resolved into the d-enantiomer via the alpha-methylbenzylamine salt. The penultimate intermediate, 2-mercaptopilocarpine, was desulfurized by oxidation with dilute hydrogen peroxide, minimizing isomerization to isopilocarpine. Procedures for the analysis of pilocarpine-isopilocarpine mixtures by high-pressure liquid chromatography are also described.

4-Butyrolactone↗